Antipsoriatic agent

ABSTRACT

An object of the present invention is to synthesize a pharmaceutical effective for the treatment of psoriasis.  
     A therapeutic agent for psoriasis, comprising 2β-(3-hydroxypropyloxy)-1α,25-dihydroxyvitamin D 3  as an active ingredient, is provided by the present invention.

TECHNICAL FIELD

This invention relates to a therapeutic agent for psoriasis, comprisinga vitamin D derivative as an active ingredient.

BACKGROUND ART

Psoriasis is a chronic intractable skin disease, characterized byabnormal proliferation of skin cells. Its etiology is not yet clear, butthe deviation of skin cells from the normal growth mechanism anddifferentiation mechanism is considered to be a main cause. There hasbeen an increase in the number of cases of psoriasis in recent years,and most psoriatic cases involve well-demarcated papules or erythemaswith thick scales, and follow a chronic course. This type of psoriasisis called psoriasis vulgaris. Unlike psoriasis vulgaris, psoriasispustulosa forms pustules on erythemas. Psoriasis pustulosa is classifiedinto generalized (Zumbush's) pustular psoriasis which occurs over wideareas and involves systemic symptoms, and localized (Barber's) pustularpsoriasis which develops over small areas, such as the hands or feet.Psoriasis may occasionally cause redness, swelling, degeneration orankylosis of joints of the hands or feet, elbow and knee. This is calledarthritic psoriasis.

Treatments for psoriasis include external application ofcorticosteroids, photochemotherapy (PUVA), and oral administration ofretinoids. However, these treatments have not always had a satisfactorytherapeutic effect. In recent years, 1α,25-dihydroxyvitamin D₃,calcipotriol, etc., which are known as active vitamin D₃, have beenshown to have the activity of suppressing the proliferation ofkeratinocytes, and to be useful as therapeutic agents for psoriasis(European Patent Publication No. 129003, “Vitamin D in Dermatology”,edited by Knud Kragballe (2000), Marcel Dekker Inc., and Drugs 43(3),415-429 (1992)). However, more potent and more effective pharmaceuticalsare still desired.

2β-(3-Hydroxypropyloxy)-1α,25-dihydroxyvitamin D₃, which is a vitamin Dderivative having a substituent at the 2-position, is known to have acalcium regulating action (JP 61-267549 A) and an osseous unionpromoting action (JP 08-12580 A). However, its use as a therapeuticagent for psoriasis has not been known at all.

DISCLOSURE OF THE INVENTION

As described above, existing treatment methods and therapeutic agentsfor psoriasis have not been entirely satisfactory, and more potent andeffective treatments and therapeutic drugs have been desired. It is anobject of the present invention to provide an effective therapeuticagent and treating method for psoriasis.

The inventor of the present invention investigated the suppressingaction of 2β-(3-hydroxypropyloxy)-1α,25-dihydroxyvitamin D₃ on thekeratinocyte proliferation. The inventor has found that surprisinglythis compound has a very potent suppressing action, in comparison withactive vitamin D₃, and has accomplished the present invention.

That is, the present invention provides a therapeutic agent forpsoriasis, which agent comprises a compound represented by the followingFormula (I)

as an active ingredient.

The therapeutic agent for psoriasis according to the present inventionpreferably suppresses the proliferation of keratinocytes.

The therapeutic agent for psoriasis according to the present inventionmay be administered to animals as well as humans.

According to another aspect of the present invention, there is provideda method for the treatment of psoriasis in a human or an animal, themethod comprises administering a therapeutically effective amount of acompound represented by the following Formula (I)

to a human or an animal in need of such treatment.

According to still another aspect of the present invention, there isprovided use of a compound represented by the following Formula (I)

in production of a therapeutic agent for psoriasis.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing the effect of suppressing the proliferation ofcultured human keratinocytes by an active vitamin D₃ (designated as“1,25D3” in the figure) and2β-(3-hydroxypropyloxy)-1α,25-dihydroxyvitamin D₃ (designated as “ED-71”in the figure). In the figure, filled rhombuses (♦) represent the activevitamin D₃, and open circles (◯) represent ED-71.

PREFERRED MODE FOR CARRYING OUT THE INVENTION

The entire disclosure of Japanese Patent Application No. 2002-224297, anapplication as the basis for priority claimed by the presentapplication, is incorporated herein by reference in its entirety.

The compound represented by the Formula (I), namely,2β-(3-hydroxypropyloxy)-1α,25-dihydroxyvitamin D₃, can be synthesized,for example, by the method described in JP 61-267549 A, although themethod for its synthesis is not limited.

The therapeutic agent for psoriasis according to the present inventioncan be administered orally, parenterally (subcutaneous injection,intravenous injection, intramuscular injection, intraperitonealinjection, etc.), enterally, or topically. Topical administration, suchas by an agent for external use, is preferred, but systemicadministration as an oral agent or an injection may be performed. It isalso possible to use a mode of administration, such as oraladministration, injection, or external use, in a suitable combination.

The therapeutic agent for psoriasis according to the present inventionmay contain a pharmaceutically acceptable carrier or diluent in additionto the active ingredient. Examples of the carrier or diluent arevehicles (starch, lactose, etc.), disintegrants (alginic acid, etc.),tablet lubricants (stearic acid, talc, etc.), binders (starch, etc.),antioxidants (ascorbic acid, etc.), emulsifiers (polysorbate, etc.),surfactants (sorbitan monoesters, etc.), preservatives (benzoic acid),perfumes, and colorants. Other therapeutic ingredients may be containedfurther.

The therapeutic agent for psoriasis according to the present inventioncan be appropriately formulated according to the route ofadministration, such as oral administration, enteral administration,parenteral (including subcutaneous, intramuscular, and intravenous)administration, or external use.

For oral administration, such formulations as tablets, capsules,powders, granules, syrups, and elixirs are available. For parenteraladministration, such formulations as injections (e.g., liquids orsuspensions) are available. For external use as topical administration,such formulations as ointments, creams and lotions are available. Forenteral administration, such formulations as suppositories and enemasare available.

The dose of the therapeutic agent for psoriasis in the present inventioncan be selected, as appropriate, according to the state of disease, thebody weight and age of a subject to be treated, the route ofadministration and the dosage form of the agent of the presentinvention. For administration to animals, the dose is greatly affectedby the body weight of individual animals. In the human adult, the usualoral dose of 2β-(3-hydroxypropyloxy)-1α,25-dihydroxyvitamin D₃, as theactive ingredient, can be selected from the range of 0.0001 μg to 1,000μg, preferably 0.001 μg to 100 μg, more preferably 0.01 μg to 10 μg,most preferably 0.1 μg to 1 μg, per day, and this dose can be used oncedaily or as two to three divided doses per day. For external medicine,such as an ointment, the dose of this compound as the active ingredientcan be selected from the range of 0.0001 μg to 10,000 μg, preferably0.001 μg to 1,000 μg, more preferably 0.01 μg to 100 μg, most preferably0.1 μg to 25 μg, per day.

EXAMPLES

The present invention will be described in further detail by thefollowing Examples and Manufacturing Examples.

Example 1

The effect of suppressing the proliferation of cultured humankeratinocytes by 2β-(3-hydroxypropyloxy)-1α,25-dihydroxyvitamin D₃(hereinafter referred to as “ED-71”) was investigated.

KGM-2 culture medium was added to each well of a 96-well plate (COSTAR3595), and adult-human-derived keratinocytes (Clonetics) were seeded ata cell count of 1×10³/well. Then, active vitamin D₃(1α,25-dihydroxyvitamin D₃, produced by Solvay Pharmaceuticals) or ED-71(produced by Chugai Seiyaku) was added to each well in a finalconcentration of 1×10⁻¹⁰ mol/L, 1×10⁻⁹ mol/L, 1×10⁻⁸ mol/L, or 1×10⁻⁷mol/L. The cells were cultured in the KGM-2 culture medium at a cellconcentration of 1×10³/200 μl/well for 3 days at 37° C. in an atmosphereof 5% CO₂ and 95% air. [³H]thymidine was added in an amount of 7.4kBq/well, and the cells were further cultured for 1 day. The culturemedium was removed, and the cells were stripped off using 0.05%trypsin/EDTA (GIBCO BRL), and the amount of [³H]thymidine taken up bythe cells was measured with a liquid scintillation counter (1450MICROBETA, Wallac). The cells cultured and treated in the same manner asdescribed above, except for the addition of the active vitamin D₃ orED-71, were used as a control.

The results are shown in FIG. 1. In FIG. 1, the [³H]thymidine uptakeinto the cells treated with each drug is expressed as a percentage ofthe [³H]thymidine uptake into the control cells.

As shown in FIG. 1, the IC₅₀ (mol/L) value of the active vitamin D₃ was3.05×10⁻⁸ mol/L, while the IC₅₀ (mol/L) value of ED-71 was <1.0×10⁻¹⁰mol/L.

In accordance with the following calculation equation, the humankeratinocyte proliferation suppressing activity of ED-71 was calculatedas a relative value with respect to the active vitamin D₃. This activitywas found to be 305.23 or more.Relative value=(IC ₅₀ value of active vitamin D ₃)/(IC ₅₀ value ofED-71)This outcome shows that ED-71 has a very potent keratinocyteproliferation suppressing action, as compared with active vitamin D₃.

Example 2

The effect of ED-71 administered percutaneously and orally wasinvestigated using hairless mice.

Percutaneous administration of a vitamin D₃ derivative in hairless micewas reported to cause hyperplasia of the epidermis (British Journal ofDermatology 1995; 132; 841-852). Following a single percutaneous dose ofactive vitamin D₃ (1α,25-dihydroxyvitamin D₃) and ED-71 administered tohairless mice, ED-71 thickened the epidermis in a lower dose than thedose of active vitamin D₃. When active vitamin D₃ and ED-71 wereadministered orally to hairless mice for 4 days, ED-71 thickened theepidermis in a lower dose than the dose of active vitamin D₃. Theseresults suggested that ED-71, administered percutaneously or orally,would be effective.

Preparation Example 1

ED-71 (0.5 mg) is mixed with a hydrophilic ointment having the followingformulation to obtain a hydrophilic ointment containing 0.5 μg of ED-71per gram: White petrolatum 250 g Stearyl alcohol 220 g Propylene glycol120 g Sodium lauryl sulfate 15 g Ethyl parahydroxybenzoate 0.25 g Propylparahydroxybenzoate 0.15 g Purified water appropriate amount Totalamount 1000 g

Preparation Example 2

ED-71 (1.0 mg) is dissolved in 60 g of a triglyceride of a middle chainfatty acid, and 30 mg of sorbic acid is added as a stabilizer. Themixture is processed in accordance with a conventional method using agelatin shell soft capsule manufacturing machine to obtain soft capsulescontaining 1.0 μg of ED-71 per capsule.

INDUSTRIAL APPLICABILITY

As described above, 2β-(3-hydroxypropyloxy)-1α,25-dihydroxyvitamin D₃has an excellent keratinocyte proliferation suppressing action. Thetherapeutic agent of the present invention, comprising this compound asan active ingredient, is expected to be useful for treatment ofpsoriasis.

1. A therapeutic agent for psoriasis, comprising a compound representedby the following Formula (I)

as an active ingredient:
 2. The therapeutic agent for psoriasisaccording to claim 1, said therapeutic agent suppressing proliferationof keratinocytes.
 3. A method for the treatment of psoriasis, comprisingadministering an effective amount of a compound represented by thefollowing Formula (I)

to a subject in need of such treatment.
 4. The method according to claim3, wherein proliferation of keratinocytes is suppressed.